Project Summary Despite widespread use of combination antiretroviral therapy (cART), nearly half of HIV+ Americans will experience HIV-related neurological comorbidities that negatively impact daily functioning and clinical outcomes. Alterations in brain structure and function are consistently linked to HIV-associated neurocognitive disorders (HAND), but the mechanisms through which HIV causes alterations in neural networks and associated cognitive function are not well characterized. Marijuana use, which is disproportionately prevalent among HIV+ persons, may increase the risk of HAND. Our preliminary work suggests that co-occurring marijuana use and HIV infection intensifies dysfunction in major neural networks, including white matter abnormalities and decoupling of functional activation patterns. Capitalizing on a strong foundation of neurobehavioral research on drug addiction and HIV/AIDS by our multidisciplinary team, the proposed research will apply connectomic analyses to achieve the following aims: (1) examine the independent and interactive effects of HIV and marijuana on structural and functional organization of the brain; (2) investigate the longitudinal relationship between network-level disruptions in brain organization and cognitive impairment; and (3) use machine deep learning algorithms to develop individualized prediction models for HAND diagnosis and severity based on multimodal graph features. Using a cross-lagged panel design, 200 adults stratified by HIV and marijuana status (4 groups) will have multimodal MRIs and cognitive testing at baseline and 1 year later. The central hypothesis is that marijuana use will exacerbate structural and functional disruptions in brain organization that underlie the expression and progression of HAND. Our proposal responds directly to RFA-18- 610, which highlights the need for studies on ?the underlying mechanisms whereby drugs of abuse and HIV infection interact to impair CNS functions mediated through altered neuronal networks.? This research uses a team science approach to address high priority topics for AIDS-designated funding, including neurological complications [NOT-15-137]. Building upon a sound premise and robust preliminary data, this innovative project has strong potential to identify appropriate neural biomarkers that may aid in the diagnosis and monitoring of HAND in persons with chronic substance use disorders and serve as targets for novel clinical interventions. In addition, our classification models are expected to provide a generalizable framework applicable to individual patients for tailoring of treatment approaches.